Co-administration of vaccines with compounds that can enhance the immune response against the antigen of interest, known as adjuvants, has been extensively studied. In addition to increasing the immune response against the antigen of interest, some adjuvants may be used to decrease the amount of antigen necessary to provoke the desired immune response or decrease the number of injections needed in a clinical regimen to induce a durable immune response and provide protection from disease.
Aluminum-based compounds were determined to possess adjuvant activity over 60 years ago (for review, see Lindblad, E. B. Immunol. and Cell Biol. 82: 497-505 (2004); Baylor et al. Vaccine 20: S18-S23 (2002)). Aluminum adjuvants are generally regarded as safe when used at appropriate dosages. Due in part to their low cost and long history of use in human patients, aluminum salt adjuvants are the most prevalent adjuvants used in human vaccines.
Aluminum salt adjuvanted vaccines are typically formulated as liquids which are extremely sensitive to temperature changes, such as heating or freezing. Freezing aluminum-salt containing vaccines causes irreversible damage to the physical structure of the aluminum salt, which results from adjuvant particle agglomeration. This leads to loss of adjuvant activity and, ultimately, a loss of vaccine potency. For this reason, such vaccine formulations must be maintained within a narrow temperature range, preferably between 2° C. and 8° C., which requires a robust cold chain during vaccine transportation and storage. Maintenance of the cold chain is not always economically feasible, especially in developing countries. Additionally, accidental freezing of aluminum salt adjuvanted vaccines is a common problem in both developing and developed countries (Clapp et al., J Pharm. Sci. 100(2): 388-401 (2011); Matthias et al., Vaccine 25(20): 3980-86 (2007)). Frozen vaccine shipments must be discarded at an enormous cost. Also of concern is the potential for previously frozen, lower potency vaccine to be inadvertently given to patients, leading to decreased efficacy.
Several approaches have been proposed to address the problems associated with maintaining the proper temperature for aluminum salt containing vaccines. One potential solution is to prevent freezing through the addition of formulation components such as propylene glycol, polyethylene glycol or glycerol (Braun, L. J. et al., Vaccine 27: 4609-4614 (2009); Braun et al., Vaccine 27: 72-79 (2009)). Braun et al., supra, have shown that propylene glycol can prevent freeze-induced adjuvant agglomeration in certain vaccines, even at concentrations too low to prevent freezing.
The use of freeze-dried instead of liquid vaccine formulations may alleviate some issues associated with transportation and storage of a vaccine; however, the process of freeze-drying is also associated with adjuvant particle aggregation and loss of potency (Maa et al., J. Pharm. Sci. 92(2): 319-332 (2003)). Clausi et al. (J. Pharm. Sci. 97: 2049-61 (2008)) and Randolph et al. (WO 2008/118691) have shown that aluminum adjuvant aggregation during freezing and lyophilization can be mitigated through the addition of high concentrations (e.g. 15%) of trehalose to the formulation. Wolff et al. (Colloids & Surfaces A: Physiochem Eng. Aspects 330: 116-126 (2008)) also suggest the use of high concentrations of trehalose to protect aluminum containing vaccines from cold stress. Also proposed by Wolff et al. as candidate formulation components for preventing aluminum adjuvant aggregation were PVP K 25, HES 450 and 200, saccharose and sorbitol. Mizuno et al. (EP Patent No. 0 130 619 B1) propose the use of at least one amino acid or salt thereof in combination with at least one saccharide and at least one colloidal substance.
It would be useful to develop liquid vaccine formulations wherein the vaccine antigen is adsorbed onto an aluminum adjuvant, wherein the formulation is able to retain its physical and immunological properties upon freezing or lyophilizing.